13-monomethyl steroids



M. R. EHRENSTEIN l3-MONOMETHYL STEROIDS Filed May 19, 1948 Nov. 2l, 1950 JNI/ENTOR.

Mciximiiion R. Ehrensiein ATTORNEYS llil Patented Nov. 21, 1950 13-MONOMETHYL STEROIDS Maximilian R. Ehrenstein, Philadelphia, Pa., as-

signer to The Trustees of the University of Pennsylvania, Philadelphia, Pa., a corporation of Pennsylvania Application May 19, 1948, Serial No. 28,034

2 Claims.

This invention relates to certain new chemical compounds believed variously to have therapeutic value in the endocrine eld and variously to have value as intermediates; and method for their production.

More specifically, the new chemical compounds contemplated by this invention Will include the new compound -norprogesterone, related compounds and various intermediates, which are produced in the course of its preparation by the method according to this invention.

The new compound, 10-norprogesterone, and related compounds, have been found to have progestational activity rendering them useful therapeutically in the endocrine eld. The new compounds comprising intermediates formed in the course of preparation of lll-norprogesterone will nd utility in connection with the preparation of 10-norprogesterone and variously may be found to have therapeutic value.

The particular structure of the new compound, 10-norprogesterone, and the structure of the novel compounds comprising intermediates formed in the preparation of 10norprogesterone and the procedure according to the method of this invention is illustrated in the scheme shown in the accompanying drawing, with reference to which the nature of the several novel compounds and the details of the method will be described.

In the scheme:

The formulae illustrate the structures of 10- norprogesterone and of the several intermediates formed in the course of its preparation and the several steps of the method according to this invention are broadly indicated.

In the scheme the starting material or compound is indicated at A. This material, a saturated dicarboxylic acid having the formula CzoHaoOs (estrane 3,5 diol 10,17-dicarboxylic acid), has heretofore been prepared and is described, for example, by Butenandt and Gallagher, Ber. 72, p. 1866 (1939); Chem. Abstr. 34, p. 773 (1940).

Proceeding now according to the method of this invention, as indicated in the scheme, the compound B is formed by acylation of the startingr compound A to protect the hydroxyl group at carbon atom 3, The acylation of the compound A is, for example, effected by treatment with an acid anhydride, as, for example, acetic anhydride, propionic anhydride, or other suitable anhydride which will protect the hydroxyl group at carbon atom 3.

As exempliiying the procedure for acylation of the compound A, using acetic anhydride, a solu- (Cl. E-397.4)

tion of 0.450 g. of recrystallized estreme-3, 5-dio1 10,17-dicarboxylic acid in 4.5 cc. of acetic anhydride is reuxed (metal-bath, 14o-150 C.) for 30 minutes, after which 4.5 cc. of glacial acetic acid and 2.7 cc. of water are added to decompose anhydrides and the solution then heated on a water bath for about one hour. On completion of the heating the solvent is removed in vacuo (50 C.) and the sirupy residue taken up in ether and the solution extracted twice With ice cold dilute sodium carbonate. The combined extracts are acidied by adding without delay ice cold dilute hydrochloric acid which will cause a White flocculent precipitate to appear. The suspension is then extracted three times with ether and the combined ether extracts washed several times with small quantities of water. After drying and filtering, evaporation of the ether yields a product, usually obtained as a foamy, colorless glass. This product, which cornprises the compound B, is then, for analysis, dried at C. under slight vacuum in order to avoid possible decomposition and analyzes as follows:

Calculated for CzzHazOfz (Monoacetate): C, 64.66; H, 7.90. Found: C, 64.20; H, '7.36.

Proceeding now from the compound B to the compound C, which, for example, may be 3- acetoxy-10-noretiocholenic acid (3-acetoxyestrene-l'-carboxylic acid), the compound B is subjected to heating in a high vacuum to effect dehydration and decarboxylation of the compound B. Preferably the compound B will be subjected to distillation in a high vacuum.

As exemplifying the procedure for the preparation of compound C from the compound B, Where the compound B is, for example, an acetate, 0.590 g. of the crude compound B is transferred into a high vacuum retort by means of ether. After careful removal of the solvent, a foamy glass remains, which, on gentle heating in a high vacuum to a temperature of 80-120 C., is almost completely liqueed or sintered. The material thus obtained, essentially free from solvent, is subjected to distillation in a high vacuum. In eiecting the distillation the temperature is raised fairly quickly to about C. where gas evolution will be observed. Subsequently, the temperature is raised slowly, say within a period of about one hour, to 250 C. and then quickly raised to about 290 C. and the distillation thereafter interrupted. The distillate, usually a slightly yellow, brittle glass, is subjected to another distillation under practically identical conditions,

it being noted that in the redistillation there is no notable gas evolution. The product usually is a slightly yellow, brittle glass and gives a strong positive reaction with tetranitromethane. Analysis shows the following:

Calculated fOr C21H3004I C, 72.78; H, 8.73. Found: C, '73.36, 72.78; H, 8.30, 8.51. Titration: 11.2 mg. of the product required 3.31 cc. of 0.01 N NaOH; calculated for monocarboxylic acid CziHsoOi; 3.23 cc.

In this product as illustrated in the scheme the es double bond may be in the 5,6 positionfinthe 5,10 position, or in the 4,5 position, or the product may be a mixture of any two or allof these isomers hereinafter indicated by reference to and/or isomers. However, no attempt was made to separate these isomers.

Proceeding now for the preparation of the coinpound D, which, for example, may be B-acetoxyl-noretiocholenic acid chloride (3-acetoxyestrene-l'l-carboxylic acid chloride) and/or isomers, the compound Cis directly transformed into the correspondingacid chloride rand/ or isomers .by means of, for example, thionyl chloride, phosphorous oxychloride or phosphorous pentachloride. It will be understood that the compound D may be prepared as an acid bromide by using an equivalent bromide `in place of the aforementionedchlorides.

As exemplifying the procedure for the preparation of 'the compound D from the compound C, a

purified, colorless thionyl chloride is prepared,`by distilling pure commercial thionyl chloride (Eastman), of a :slightly yellow color, over quinoline and then over linseed oil. To 200 mg. of the compound C, and/or isomers, is added in a cold room 1.0 cc. ofthe pur-iedthion'yl chloride. The mixture is allowed to stand under anhydrous conditions in the cold room (about 2 C.) for a period of `about 50 minutes and then at room temperatermediates useful for its preparation and method for the preparation thereof, forms the subjectmatter of an application for patent filed by me Serial No. 584,623, led March 24, 1945.

The preparation of the compound E', or related compounds indicated above and/or isomers, from the compound D is accomplished by treatment of the compound D or related compounds indicated above arid/or isomers with a methylzinc halide, preferably methylzinc iodide or with dimethyl cadmium.

An exemplifying procedure for transforming, for example, the compound D to, for example, the compound E, a turning, colorless solution of methylzinc iodide is prepared by adding a zinccopper couple, prepared from 2 g. of zinc (Zinc Reagent-Merck, Mossy cut in small pieces of 1-3 mm. size) and 0.2 g. of copper powder, by the method of Job and Reich, Bull. Soc. Chim. [4], 33, 1414 (1923), and an iodine crystal to a mixture of 2.33 g. of methyliodide (Eastman, pure), 0.5 cc. .of dry alcohol-free ethyl acetate, and 1.0 cc. of vdry toluene. The mixture was heated (reflux condenser) under anhydrous condictions in a metal bath to 80 C. Over a period of 11/2 hours the `temperature was gradually raised to 120 C., where it was kept for 45 minutes. After cooling to room temperature the mixture was diluted with 1.0 cc. of toluene.

The organo-zinc solution is decan'ted from excess metal and ice-cooled, then a solution of the compound D, prepared from 200 mg. of compound C, .in 1.0 cc. of dry benzene is slowly added. The mixture is allowed to stand at room temperature (24 C.) for about 30 minutes. After cooling with ice, water is gradually added, which results in the formation of Aa thick precipitate which is brought into solution by adding an excess of .N sulfuric acid until acid to Congo. The reaction mixture ture (20 C.) for about 31/2 hours, which usually 4c is then @Xtmcted With an ample? quantity Ofethel" resulte in the formation of .an Olive green s01u and the ether extract washed with a concentrated tion The Solution thus formed 'is brought to solution of ammonium sulfate, water, a solution dryness in vacuo (40 C.) under anhydrous con- O'f N sodiurnhydroxide and then three times with dimens The residue is then dried Overnight in small quantities of water (neutral ether extract). a Vacuum desiccater (P2O5KOH). 4: The neutral ether extract is dried with sodium The acid chloride, or the bromide thus pre sulfate, brought to dryness in vacuo (40 C.) pared serv-es for the production of the compound and the resldue @fled 1n a vacuum deswcator E, as, for example, V3-acetoxy-lll-norpregene-ZO- (P2O5;KO H). The residue is usually an Orangeone and/orsomerscolored viscous oil. amounting to about 135 me,

The compound D, or related compounds indi- 50 The. neutral TSdue iS .Subjefled tochromatocated above and/or isomers, is of value Anot only graphlc adsorption by dissolving it in mixture as an intermediate for the preparation Gf `the of 10 cc. of benzene and 25 cc. of petroleum ether novel compound lil-norprogesterone according to and Subsefllleltly lfllg through a GOlLlmn -Of the method 0f this invention, but Hkewise is 6.0 g. of aluminum oxide. The original solution useful for the preparation of the novel compound 55 1S passed thl'Ough Wlthln about two hours and 10-nor-'ll-desocycorticosterone acetate, and the eluadates each within 15 minutes. The folwhich novel compound, together with Various inlowing fractionation is obtained.

Weight of Ftgn Solvent Residue, Appearance of Residue Ing,

10 cc. Benzene-F25 cc. petr. ether (original so1ution) 13. 0 colorless sticky oil. 6 cc. benzene-H4 cc. petr. ether. 46.1 slightly yellow sticky oil. '8 cc. benzene+l2 cc. petr. ether 21.1 colorless resin. 10 cc. benzene-H0 cc. petr. ether. 11.4 Do. I3 ce. benzene-H cc. petr. other 6. 8 D0. 17 cc. benzene-|-3 cc. petr. ether- 5. 9 Do. 20 cc. benzene 4.6 Do. dn 2.3 D0. 17 cc. bcnzene-icc. ether.-- 4. 2 Do. 13 cc. benzene-H cc. ether 1. D Dc. 10 cc. benzene-H0 cc. ether 1. 0 Do.

5 cc. benzenc+l5 ccA ether 0.5 20 ce. ether 0. 4 14 do V1.1 Do. 15-- 1'9 cc. ether-|41 cc. methanol 6.4 yellow resin. `16 30 cemethannl 10.6 Whitish-brownish residue.

Total 137.3

Fractions 2-8, inclusiveof the'chromatogram (98.2 mg.) are combined and subjected to a distillation in high vacuum, heating to 110 C. within minutes and gradual raising of the temperature to slightly above 200 C. within a period of one hour, which yields about 87 .5 mg.

The major part of the distillate v(76.8 mg.) is subjected to further puriiication by means of Girards reagent T (betaine hydrazide hydrochloride) by the addition of 110 mg. of Girards reagent and 0.06 cc. of glacial acetic acid to the distillate dissolved in 1.0 cc. of methanol and refluxing on a water bath for 1 hour and then allowing to stand in the cold room for two days. Thereafter the mixture is cooled to 5 C. and about 1 g. of ice and an ice cold solution of 0.05 g. of sodium carbonate in 1 cc. of water is added. The mixture is then quickly extracted twice with ether in the cold room and the combined ether phases washed at room t-vmperature successively with water, a solution of N sodium carbonate and four times with water. After drying with sodium sulfate and removal of the ether, an almost colorless resin is usually obtained (non-ketonic fraction).

The aqueous phase is then made acid to Congo by adding 1 cc. of 4 N sulfuric acid in the cold room and the resultant mixture extracted four times with ether at room temperature and the combined ether phases washed successively with water, a solution of N sodium carbonate and four times with water. After drying the ethereal solution with sodium sulfate and subsequent removal of the ether an almost colorless, soft resin (ketonic fraction) is usually obtained. An additional amount of the ketonic fraction can be obtained by subjecting the non-ketonic fraction above to treatment with Girards reagent under the conditions indicated above. l

The almost colorless, soft resin (ketonic frac- .tionz about 47.4 mg.) obtained above is subjected to distil1ation in a high vacuum, yielding as the distillate usually a slightly yellow, viscous resin which comprises the compound E and/or isomers.

The preparation of the compound F, 10-noranol. The mixture is reiiuxed on a water bath for 11/2 hours and is then made acid to Congo by the addition of dilute hydrochloric acid. The major part of the methanol is then removed in 5 vacuo (40 C.) and the mixture extracted with ether. The ether phase is washed with a little water, a solution of N sodium carbonate and three times with water. After drying with sodium sulfate and evaporation or" the ether, usu- 10. ally an amber colored resin comprising the compound F is obtained.

The preparation of lll-norprogesterone (compound G) from the compound F and/or isomers is accomplished by dehydrogenation of the com- 15 pound F using, for example, the method de- 2O the compound E' to the compound G, to 4 cc. of a clear solution of about 100 mg. of aluminum tert.-butoxide (Eastman) in 1.0 cc. of dry benzene is added about 29.7 mg. of the compound F dissolved in 1.2 oc. of dry acetone. The resulting solution is reiiuxed under anhydrous conditions on a water bath for a period of l() hours, during which time an additional 0.2 cc. of dry acetone is added. The solution is permitted to stand at room temperature overnight, then an ample amount of ether and thereafter some N sulfuric acid are added to the solution. The ether phase is separated and Washed with a dilute solution of` sodium bicarbonate and three times with water. After drying with sodium sulfate and removal of the ether a yellowish, soft resin is usually obtained amounting to about 30.4 mg.

- The resin thus obtained is purified by chromatographic adsorption by dissolving it in a mixture of 7.5 cc. of benzene and 22.5 cc. of petroleum ether and by subsequently iiltering said solution through a column of 2.0 g. of aluminum oxide: during a period of about three hours, the eluents4 being passed through each over a period of 30 minutes. The following chromatographic. fractionation is obtained:

No. of Weight of Frac- Solvent Residue, Appear-ne" of tion Mg. es] ue 7.5 ce. benzene-+225 cc. petr. ether 1. 9 colorless resin.

(original solution) 2.5 cc. benzene-H5 cc. petr. ether... 0. 6 colorless residue. 3.5 cc. benzene-I-.5 cc. petr. ether 0. 2 Do. 5 cc. benzene-F5 cc. petr. ether.-. 1. 4 Do. 7 cc. benzene-P3 cc. petr. ether.. 4. 3 colorless resin. 9 cc. benzene-l-l cc. petr. ether. 4. 1 Do. l0 cc. bomen@ 2. 2 Dc. rln 0.9 Do.

8 cc. benzenc+2 cc. ether 2. 4 colorless glass. 6 cc. benzene-H cc. ether 0. 6 colorless residue. 4 cc. benzene-H3 cc. ether.-- 1. 7 colorless resin. 12 10 cc. ether 2.1 Do. l? dn 0.2 D0. 14 7.5 cc. ether+2.5 cc. methanol 5. 4 light yellow glass. 15 10 ce. methanol 3. 0 Whltish IllaSS.

Total 31.0

The fractions 4-8, inclusive, of the above 6L chromatogram are combined (about 12.9 mg.)

and subjected to distillation in a high vacuum, heating to 115 C. within about 10 minutes, and then gradually raising the temperature to slightly above 200 C. within a period of 40 minutes.

The distillate, comprising l-norprogesterone, is usually an almost colorless (very pale yellow) soft resin which analyzes as follows:

Calculated for C2oH2sO2Z C, '79.94; H, 9.40,

FOund: C, 79.12; H, 9.40.

7 The compound is further characterized by its ultra-violet absorption spectrum:

max=238.5 mp.; e: 16560 By reference to the scheme shown in the drawing it will be appreciated that from the broad standpoint this invention is not limited in the case of compounds D, E, F and G to compounds having the grouping COCl or COCHa at carbon atom l1, but to the contrary contemplates also those compounds having the structure of compound D except for the fact that they have the grouping COX at carbon atom Il, Where X is chlorine or bromine, and also those compounds having the structure of compounds E, F and G except for the fact that they have the grouping COR at carbon atom Il, where R is an alkyl group containing not more than ten carbon atoms, for example, a methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, nonyl, decyl group, a benzyl group or a phenyl group.

The compounds having the indicated grouping COR. at carbon atom l? may be formed by treating the compound D to form the compound AE as described above except for the use of an alkyl, benzyl or phenyl zinc halide or cadmium halide corresponding to the COR group desired in place of a methyl zinc halide or dimethyl cadmium.

The compounds C-E, inclusive, according to this invention will more particularly have the grouping RO at carbon atom 3, where R is an aliphatic or aromatic acyl group, for example, a benzoyl group, a phenyl acetyl group or an aliphatic acyl group having 2-6 carbon atoms, as a propionic group, a butyric group, a valerio group or a caproic group. The compounds having RO at carbon atom 3, respectively, will be formed as described above by acylation of compound A using the reagent corresponding to the desired substituent for R in place of acetic anhydride, it being apparent that the OH group at carbon atom 3 in compound A is highly reactive. Alternatively, a chloride instead of an anhydride may be used to introduce the desired group R.

Specific examples of the compounds according to this invention, where the grouping COR at carbon atom l1 and the grouping RO at carbon atom 3 are as given above specifically, will be obvious and will be had by substitution in the structural formulae shown in the attached scheme of respectively the several substituents given for R. and R', respectively.

It will be understood, with reference to the several compounds illustrated and described above, that I do not intend that this invention or the claims appended hereto shall be limited to any particular conguration about any carbon atom and, in particular, about carbon atoms 3, I0, I4 and l1.

This application is a continuation-impart of my application Serial No. 647,966, led February 14, 1946, now abandoned, which is a division of my application Serial No. 584,623, illecl March 24, 1945, now abandoned.

What I claim and desire to protect by Letters Patent is:

1. A 13-monomethy1- cyclopentanopolyhydrophenanthrene having the following structure:

ooRl

HO- 3 5 T -A=ccrbon to carbon double bond W extending from carbon atom 5 HO '-6- -A=a carbon to carbon double bond W extending from carbon atom 5 MAXIMILIAN R. EHRENSTEIN.

No references cited. 

1. A 13-MONOMETHYL - CYCLOPENTANOPOLYHYDROPHENANTHRENE HAVING THE FOLLOWING STRUCTURE: 